Hepatology (Baltimore, Md.) 2017 09 13() doi 10.1002/hep.29523
The NLRP3 inflammasome, a caspase-1 activation platform plays a key role in the modulation of liver inflammation and fibrosis. Here, we tested the hypothesis that interleukin 17 (IL-17) and tumor necrosis factor (TNF) are key cytokines involved in amplifying and perpetuating the liver damage and fibrosis resulting from NLRP3 activation. To address this hypothesis gain of function Nlrp3(A350V) knock-in mice were bred onto il17a and Tnf knockout backgrounds allowing for constitutive Nlrp3 activation in myeloid derived cells in mice deficient in IL-17 or TNF. Livers of Nlrp3(A350V) knock-in mice exhibited severe liver inflammatory changes characterized by infiltration with neutrophils, increased expression of CXCL1 and CXCL2 chemokines, activated inflammatory macrophages and elevated levels of IL-17 and TNF. Mutants with ablation of il17a signal showed fewer neutrophils when compared to intact Nlrp3(A350V) mutants, but still significant inflammatory changes when compared to the non-mutant il17a knockout littermates. The severe inflammatory changes associated with mutant Nlrp3 were almost completely rescued by Tnf knockout in association with a marked decrease in circulating IL-1β levels. Intact Nlrp3(A350V) mutants showed changes of liver fibrosis, as evidenced by morphometric quantitation of Sirius red staining and increased mRNA levels of profibrotic genes including CTGF and TIMP-1. Il17a lacking mutants exhibited amelioration of the aforementioned fibrosis, while Tnf deficient mutants showed no signs of fibrosis when compared to littermate controls.
Our study uncovers key roles for TNF, and to a lesser extent IL-17, as mediators of liver inflammation and fibrosis induced by constitutive NLRP3 inflammasome activation in myeloid derived cells. These findings may lead to novel therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis in various liver pathogenesis driven by NLRP3 activation. This article is protected by copyright. All rights reserved.